DESCRIPTION (provided by applicant): Filopodia are finger-like cellular protrusions hypothesized to act as sensors that allow cells to contact and interact with their environment. Filopodia are known or hypothesized to have key roles in processes such as nerve growth, angiogenesis, wound healing, and hearing. Structurally related protrusions known as stereocilia function as mechanosensors responsible for our senses of hearing and balance, and defects in the assembly of stereocilia, or in the unconventional myosins that localize to them, cause many forms of human deafness. Although the tips of filopodia, microvilli, and stereocilia all contain a specialized structure known as the tip complex, remarkably little is known about the basic properties of the tip complex, even though it clearly represents a key site of cell contact and interaction that is also important in the formation of these protrusions. Our discovery that myosin-X (Myo10) localizes to the tips of filopodia and binds to �-integrins has led us to hypothesize that Myo10 is a central component of the filopodial tip complex, and that the tip complex is a specialized site of polymerization, adhesion, and signaling. Since very little is known about the filopodial tip complex, especially in comparison to intensively studied adhesive structures such as focal adhesions, our objective is to determine the basic properties of the filopodial tip complex and define its roles in filopodial adhesion and signaling. Our specific aims are to: 1) Determine the composition and properties of the filopodial tip complex. 2) Visualize the formation and dynamics of the tip complex and investigate its role in cell signaling. 3) Determine the functions of the filopodial tip complex in adhesion and mechanotransduction. By defining the basic properties of the filopodial tip complex, this research will provide fundamental information needed to understand key cell biological processes underlying human health and disease. In addition, studies of Myo10 and the filopodial tip complex provide a model system for understanding the functions of unconventional myosins in stereocilia and other structures based on actin bundles.

PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it investigates the molecular mechanisms by which finger-like cellular protrusions known as filopodia interact with their surroundings, a process that is critical for neural development, angiogenesis, and cancer metastasis. This research also provides an important model system for understanding the roles of myosins in hearing and human deafness. This research will thus fill critical gaps in our knowledge of the fundamental cell biological processes that underlie majo human diseases.